Results from an expanded phase 1 trial of botensilimab, a multifunctional anti-CTLA-4, plus balstilimab (anti-PD-1) for metastatic heavily pretreated microsatellite stable colorectal cancer

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oregon; chiles


Background Botensilimab (BOT), a multifunctional Fc-enhanced anti-CTLA-4 antibody has previously shown durable objective responses in 9 immunotherapy-resistant / ‘cold’ tumors. BOT is designed to enhance T cell priming, activation, and memory formation; to deplete intratumoral T regulatory cells and activate antigen presenting cells; and to improve safety by reducing complement fixation. Here we present updated efficacy and safety data from an ongoing expanded phase Ib study investigating BOT ± balstilimab (BAL; anti-PD-1) in patients with refractory metastatic microsatellite stable colorectal cancer (MSS or non-microsatellite instability-high CRC). Methods Patients received BOT 1 or 2 mg/kg every 6 weeks (Q6W) + BAL 3 mg/kg Q2W. RECIST 1.1 imaging assessments were performed at least once every 6 weeks. Primary and secondary endpoints included adverse events, objective response rate (ORR), disease control rate (DCR; best response of complete response [CR], partial response [PR], or stable disease [SD]), progression-free survival (PFS), and overall survival (OS). Results As of May 26, 2023, a total of 101 MSS CRC patients were enrolled and received at least one dose of combination treatment (intent-to-treat population; ITT). Eighty-seven were evaluable for efficacy (at least one post-baseline 6-week scan): 69 with no active liver metastases and 18 with active liver metastases. In the ITT population (N=101), median age was 54 years (range, 25–82); median number of prior therapies was 4 (range, 1–10); 25% received prior immunotherapy; 58/100 (58%) had RAS mutations, 3/71 (4%) BRAF mutations, and only 3/76 (4%) had a tumor mutational burden (TMB) of >10 mutations/Mb (none > 13). In the evaluable population without active liver metastases (n=69), RECIST 1.1 confirmed ORR was 23% (95% CI, 14–35) including 1 CR, 15 PRs, and 39 SDs; DCR was 80% (95% CI, 68–88) with 11/16 (69%) responses ongoing. The 12-month OS was 74% (95% CI, 59–84), and median OS was 20.9 months (95% CI, 20.9–NR) with a median follow-up of 9.8 months (range, 1.4–36.5). Of the 16 responders, 11/16 (69%) had RAS mutations (8 KRAS, 3 NRAS) and 1/14 (7%) had BRAF mutations. In all efficacy evaluable patients (n=87), median OS was 20.9 months (95% CI, 10.6–NR), with a median follow-up of 9.3 months (range, 1.4–36.5). The safety profile remains favorable and consistent with previously reported data across tumor types. Treatment-related adverse events (TRAEs) of any grade occurred in 88% of patients, 37% grade 3, 2% grade 4, and no treatment-related deaths. Most common all-grade TRAEs included immune-mediated diarrhea/colitis (40%; 16% grade 3; 1% grade 4), fatigue (32%), and decreased appetite (27%). Conclusions In patients with heavily pretreated metastatic MSS CRC and longer follow-up, the combination of BOT + BAL continues to show durable responses and prolonged overall survival across all subgroups, and a favorable safety profile with no new signals. This study is ongoing, and a randomized global phase 2 trial in MSS CRC patients is actively enrolling (NCT05608044). Clinical trial identification NCT03860272.

Clinical Institute


Clinical Institute

Digestive Health






Bullock AJ, Fakih MG, Gordon MS, Tsimberidou AM, El-Khoueiry AB, Wilky BA, Pimentel A, Margolin KA, Mahadevan D, Balmanoukian AS, Sanborn RE, Schwartz GK, Abou-Alfa GK, Bockorny B, Moser JC, Sharma S, Grossman JE, Rosenthal K, O’Day SJ, Lenz H-J, Schlechter BL. ESMO 25th Annual World Congress on Gastrointestinal Cancer; June 28-July 1; Barcelona, Spain. 2023: LBA-4.

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